My long-term career goal is to contribute to cancer research as an independent investigator that will lead to better ways of treating cancer. It is well known that 90% of cancer patients die because of metastasis, which results in the spreading of tumor cells to different organs such as lung and bone. As an important step towards achieving my career goal, I joined the laboratory of Dr. Joan Massague, one of the leaders in breast cancer metastasis field for my postdoctoral training. Located in the world's premier cancer research institutes, Memorial Sloan Kettering Cancer Center, this research environment provides unparalleled resources and expertise from clinicians and basic researchers. Innovative research at MSKCC is encouraged and is complemented with inputs from the tri-institutional community comprising of Rockefeller University, Weill-Cornell Medical College and clinical input from investigators from the Memorial Hospital. My work in Dr. Massague's laboratory sheds light on how the tumor microenvironment responds to chemotherapy to benefit cancer cell survival. Our evidence from animal models and clinical samples suggest that chemotherapy induces a burst of cytokines including TNF-? from several components of the tumor microenvironment such as endothelial and smooth muscle cells. An undesirable consequence of the stromal TNF-? is to boost CXCL1/2 expression in breast cancer cells. A higher level of CXCL1/2 then drives the paracrine loop involving myeloid cell-derived S100A8/9 to enhance cancer cell survival. An adverse cycle involving TNF-?-CXCL1/2- S100A8/9 could thus be expanded in response to chemotherapy. Once initiated, this chemo- protective program could become self-sustaining, leading to the enrichment of residual aggressive clones able to resist chemotherapy and thrive in the lung parenchyma and elsewhere. Obtaining a transitional award would be an ideal stepping-stone to independence with a mentored and independent phase. Based on our previous findings, my research plan critically addresses the role of the TNF-?-CXCL1/2-S100A8/9 axis in chemoresistance and metastasis in two different cancer types, breast and lung cancer. In the case of breast cancer proposed for the K99 phase, based on our work I will interrogate the link between chemotherapy, kinetics and biology of myeloid cell recruitment and metastasis progression in breast cancer models.
The second aim will focus on devising ways of targeting the TNF-?-CXCL1/2-S100A8/9 axis most effectively. During this time, I will gain training in the area of lung cancer and familiarize myself with lung cancer metastasis models. In my independent phase, I will continue to focus on the components of the TNF-?-CXCL1/2-S100A8/9 axis (GOIs) that are activated with chemotherapy or during metastasis.
In Aim 4, I will dissect the functional contribution of the GOIs in mediating chemoresistance linked metastasis.
My overall goal is to establish a research program in cancer metastasis that is linked to therapy resistance as an independent investigator, with the goal of improving the clinical management of the disease and to enhance the quality of life in cancer patients. The K99/R00 award would be ideal for such a transition into independence. Our recent work in breast cancer metastasis has shed new insights and revealed several new avenues of research areas. We show that breast cancer cells that express a particular combination of CXCL1/2 chemokines gain survival advantage in successfully evading both the genotoxic stress of chemotherapy and the environmental stress of developing metastases (Acharyya et al., submitted). Our study shows that cancer cells co-opt both immune cells and endothelial cells of the tumor microenvironment to enhance their own survival via paracrine signals (S100a8/9 factors) from these cell types. We have confirmed these experimental analyses in tissues from breast cancer patients undergoing chemotherapy. This progress has now made it possible to address a number of outstanding questions in this area proposed in this grant application. In my K99 phase, I will scrutinize the link between chemotherapy treatment, recruitment of specific immune cells and drug resistance developed in a metastatic setting. In our preliminary analysis, I have also identified small molecule inhibitors that can break this vicious cycle, augmenting the efficacy of chemotherapy. More extensive preclinical trials with multiple models and drugs will be tested to evaluate the efficacy of CXCL1/2-S100A8/9 against breast cancer metastasis in their ability for suppressing incipient metastasis in preclinical models. Our preliminary analysis also suggests relevance of this CXCL1/2-S100A8/9 tumor- stroma interaction beyond breast cancer in lung cancer. The last two aims in the R00 phase will focus on the identification of the functional role of the CXCL1/2-S100A8/9 components in promoting metastasis and chemoresistance. Such findings will be critical for devising strategies to improve the clinical management of the disease in the long run.