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Valarie M. Weaver
Born	Ottawa,Canada
Nationality	Canadian
Education	Bachelor of Science degree in Chemistry/Biochemistry at the University of Waterloo, Honors Bachelor of Science degree at the University of Ottawa,PhD in Biochemistry from the University of Ottawa
Occupation(s)	Director of the Center for Bioengineering and Tissue Regeneration, Professor
Known for	Leading interdisciplinary research in Oncology

Valerie M. Weaver is a Canadian-born multi-award-winning postdoctoral biochemist with over 20 years of experience in leading interdisciplinary research in oncology. She is currently a Professor and Director of the Center for Bioengineering and Tissue Regeneration in the Department of Surgery at the University of California, San Francisco, and manages a laboratory which specializes primarily in exploring and researching the molecular mechanisms involved in tumor evolution. Another important aim of her lab’s research is to understand how cells respond to changes in tissue mechanics, and the biochemical and biophysical properties of the extracellular matrix. Her lab operates using interdisciplinary and collaborative approaches to investigate these various research objectives, most notably by incorporating engineers to cancer research. Ultimately, she hopes to better understand the development of normal, healthy tissues and what happens to them in a diseased state, such as cancer.

Professional Life and Education

Dr. Valerie M. Weaver was born in Ottawa and earned her Bachelor of Science degree in Chemistry/Biochemistry at the University of Waterloo in 1985 and continued her education for an Honors Bachelor of Science degree at the University of Ottawa in 1986, graduating Summa Cum Laude. She further advanced her education to earn a doctorate degree, (PhD), in Biochemistry from the University of Ottawa in 1992. After obtaining her doctorate, Dr. Weaver was awarded a National Sciences Research Council fellowship to work in the Apoptosis Research Group in the Molecular Cell Biology Division at the Institute for Biological Science where she later joined the laboratory of Dr. Mina J Bissell at the Lawrence Berkeley National Laboratory at the University of California, Berkeley in the Cancer and Cell Biology Group in the Life Sciences Division.

In 1999, she worked as an assistant professor in the Department of Pathology at the University of Pennsylvania, where she also joined the Institute for Medicine and Engineering to continue and advance her studies in exploring the role of tissue architecture on breast cancer behavior using tissue-like structures called organotypic models. It was there she began conducting interdisciplinary studies with colleagues in the Department of Bioengineering on the role of extracellular matrix stiffness of breast cell behavior. This led to a landmark publication that demonstrated how tissue tension modifies integrin signaling to disrupt breast tissue morphogenesis and induce breast tumor behavior.

In 2006, Dr. Weaver moved to the University of California, San Francisco to join the Department of Surgery as an Associate Professor and became director for the Centre for Bioengineering and Tissue Regeneration. By 2010, she had become a full Professor and has cross appointments with the Department of Anatomy and the Department of Bioengineering and Therapeutic Sciences. She also became a member of the Helen Diller Cancer Center and the Eli and Broad Stem Cell Center.

Dr. Weaver is presently still a professor at the University of  California, San Francisco in the department of Surgery, Anatomy and Bioengineering and Therapeutic Sciences and also continues to be the director of the Center for Bioengineering and Tissue Regeneration in the department of Surgery. She is currently also an Ad Hoc reviewer for several distinguished journals including Cancer Research, American Journal of Cell Biology, Journal of the National Institute, European Journal of Cell Biology and many more. Furthermore, she serves on the Editorial Board for Cancer Biology and Therapy and had served as a guest editor in 2004 for the Journal of Mammary Gland Biology and Neoplasia.

A Look Into The Weaver Lab

The ECM better known as the extracellular is the non cellular component has a notable influence over factors such as cell growth, survival, migration and tissue-specific differentiation. There is various different type of receptors that are involved in the regulation of these factors including integrins, syndecans and discoidin. Weaver Lab research revolves around determining how these ECM receptors play a role in the modulation of cell fate.  The mechanical and topological properties of the matrix play a regulatory function in the above mentioned receptors which in turn will affect cell behaviour. There is two areas that are explored within the Weaver Lab. The first focuses on how the composition and organization plays a role in mammary tissue development/tumour progression. The second seeks the clarify how matrix force affects both the embryonic and adult stem cell fate.

Scientific Career

Microenvironment Rigidity

Breast Cancer

Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors.

Dr. Weaver's principal focus consists of rigidity in the extracellular matrix and how the effects of the surrounding of the cell indirectly or directly modulates the behavior of the cell itself. One of her articles published in Molecular Biology of the Cell on November 2015, focuses on this idea by discussing the issue of therapeutic drugs not being able to be consistent and eventually face resistance from the cancerous cells they target. Lapatinib, a tyrosine kinase inhibitor often used as a therapeutic agent against HER2 (+) breast cancer cells was studied. HER2-amplified cancer cells have heightened HER2 receptors which when auto phosphorylated cause a downward signal cascade eventually leading to transcription of an increase in cell proliferation, making them the cause in ~15-20% of Breast cancers. In the course of time HER2(+) cells acquire resistance to lapatinib. Weaver and her colleagues experimented the extracellular matrix stiffness in vivo via the 3D Matrigel culture which allows one to manipulate the flexibility of the gel, set at 400 pa (closely resembling that of human breast tissue) to increasing stiffness up to > 2 GPa. Furthermore, they measured the levels of coactivators and oncogenes YAP and TAZ cytosolic retention when faced with different degrees of matrix stiffness. YAP and TAZ are transcriptional coactivators which when activated by ECM change move to the nucleus and activate the proliferation and ant apoptotic actions promoting cell survival. They observed that reducing oncogenes YAP and TAZ increased the sensitivity to lapatinib and increasing matrix stiffness promoted cell cloning. Therefore, by inquiring on the factors that can potentially play a role in inducing the resistance of lapatinib in the case of HER2(+),  Dr. Weaver and her colleagues deduced that ECM stiffness modulates HER2(+) sensitivity to lapatinib by down regulating coactivators YAP and TAZ mechanisms in the Hippo signaling pathway. This study contributes to the better understanding of tumor evolution and advancement in treatment against HER2(+) cancer cells by opening up the possibility of prolonging the effects of therapeutic agents.

Oncology

Pancreatic Cancer

Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Diminished Survival.

Dr.Weaver has also completed a significant amount of research in pancreatic cancer. In this paper which was published in Cancer Cell on July 2014, she identified the importance of myofibroblasts and type 1 collagen in pancreatic ductal adenocarcinoma and recommends further testing of immunotherapeutic approaches which would be more beneficial for survival. In contrast to many other studies that suggest that myofibroblasts and type 1 collagen associated with tumor fibrosis serve an oncogenic supportive role, she suggests that myofibroblasts and type 1 collagen constitute a protective response from the host. Through various experiments including different staining methods and histopathological analyses, she demonstrates that myofibroblasts are indeed necessary for the proper immune response against the cancer. She utilized genetically engineered KPC and PKT mouse models to mimic human pancreatic cancer. Her experiments showed that myofibroblast depletion resulted in poorly differentiated tumors, reduction in type 1 collagen, suppression of angiogenesis, enhanced tumor hypoxia, and significantly diminished survival. Additionally, she proposes that chemotherapeutic drugs such as Gemcitabine and Paclitaxel may involve dual targeting of both proliferating cancer cells and proliferating myofibroblasts which may negatively impact the effectiveness of the drugs over time. Instead, she suggests that immunotherapy can be a potential treatment for pancreatic cancer as she noted increased CTLA-4 expression as a result of myofibroblast depletion. She discovered that anti-CTLA-4 antibody therapy attenuated cancer progression and prolonged survival of mice with depleted myofibroblasts. Therefore, she promotes immunotherapy as a promising treatment for patients with pancreatic cancer and urges caution when targeting carcinoma-associated fibroblasts in pancreatic ductal adenocarcinoma.

Breast Cancer

Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration.

Another of Dr. Weaver’s research objectives is to understand the correlation between the mechanical properties of the extracellular matrix, tumor grade and progression, immune cell infiltrate, breast cancer subtypes, and human breast cancer aggression. This was the principal focus in a study published by the journal of Integrative Biology, (October 2015) titled Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration where she and her team conducted biophysical analyses on different subtypes of breast cancer including Luminal A and B, Basal-like and Her2 tumors. They used Atomic Force Microscopy to measure ECM stiffness and various staining methods for detection and histological analysis. What they found primarily was that the transition from a non-malignant tissue to an invasive ductal carcinoma (IDC) corresponded to high levels of significant collagen deposition, which lead to a stiffening of the ECM through linearization and bundling. Their study also demonstrated that human tumor progression is also accompanied by increased stromal density and elevated tumor cell mechanosignaling. Based on their experimental data, they deduced that these phenotypes correlate positively with a stiffened ECM that is the most rigid at the invasive front. Moreover, amongst breast cancer subtypes, they observed that the invasive front in the most aggressive subtypes (Basal-like and Her2) was the stiffest and most heterogeneous and contained cells with the highest mechanosignaling as compared to the less aggressive subtypes (luminal A and luminal B), which suggests that tumor aggression varies based on subtypes due mainly to their ECM stiffness and levels of mechanosignaling.To further demonstrate this, they also quantified abundant infiltrating immune cells and the highest tissue levels of TGF beta signaling within the cells at the invasive front, (regardless of the subtype), and showed that both ECM stiffness and cellular TGF beta signaling correlated positively with the number of infiltrating macrophages of which many were activated.

Awards

Dr. Weaver has been the honorable recipient of various awards throughout her successful career. These are the prestigious awards that she has won.

1980s

• University of Ottawa Gold Medal Highest Academic Standing Science
• Society of Chemical Industry Prize
• Alumni & Faculty Plaque Biochemistry
• Mary Eccelstone Research Award Wyeth Canadian Society of Nutrition Science
• American Institute of Nutrition Research Award Proctor & Gamble Graduate student award

1990s

• Lawrence Berkeley National Laboratory Achievement Award

2000s

• ACS-New Investigator Pilot Project Award, UPenn Cancer Center Grant
• DOD Career Development Award
• International Society of Differentiation Young Investigator Travel Award
• DOD Scholar Award

References

1. Acerbi, I., Cassereau, L., Dean, I., Shi, Q., Au, A., Park, C., … Weaver, V. (2015). Human Breast Cancer Invasion and Aggression Correlates with ECM Stiffening and Immune Cell Infiltration. Integrative Biology : Quantitative Biosciences from Nano to Macro, 7(10), 1120–1134. http://doi.org/10.1039/c5ib00040h
2. Center for Bioengineering & Tissue Regeneration. (n.d.). Retrieved March 15, 2017, from http://weaverlab.ucsf.edu/
3. Lin, C.-H., Pelissier, F. A., Zhang, H., Lakins, J., Weaver, V. M., Park, C., & LaBarge, M. A. (2015). Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors. Molecular Biology of the Cell, 26(22), 3946–3953. http://doi.org/10.1091/mbc.E15-07-0456
4. Özdemir, B.C., Pentcheva-Hoang, T., Carstens, J.L., Zheng, X., Wu, C.C., Simpson, T.R., Laklai, H., Sugimoto, H., Kahlert, C., Novitskiy, S.V., De Jesus-Acosta, A., Sharma, P., Heidari, P., Mahmood, U., Chin, L., Moses, H.L., Weaver, V.M., Maitra, A., Allison, J.P., LeBleu, V.S., & Kalluri, R. (2014).Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Diminished Survival. Cancer Cell, 25(3),719-734. doi:http://dx.doi.org/10.1016/j.ccr.2014.04.005