Organ and mutation dependencies shaping the tumor microenvironment

Tumors are ecosystems in which cancer cells interact with diverse cell populations. In each such ecosystem, environmental conditions, cellular compositions and paracrine signaling create a distinct tumor habitat. How much the composition of the habitat is dictated by the organ versus specific mutations in the cancer cells is unknown. If different organs and mutations have common microenvironmental design principles, one could devise more general therapy. Otherwise, therapy must be mutation and organ specific. To approach this, we will focus on major cancer mutations in BRCA1/2 and on the four organs where BRCA mutations drive cancer: breast, ovary, pancreas and prostate. We will dissect microenvironments of BRCA-driven cancers in these organs using a wide arsenal of imaging, sequencing, and molecular tools, building on our recent discovery of distinct cancer-associated fibroblast (CAF) compositions in BRCA-mutated breast cancer. To untangle complexity, we will establish a new approach to calibrate mathematical models on ex-vivo cocultures, and use it to identify testable targets. First, we will define the configuration of CAF subsets in the four organs, comparing BRCA-mutated to BRCA-WT human tumors (Aim 1). To unravel signaling loops common and different between organs, we will explore fibroblast dynamics in normal tissues and their diseased counterparts by ex-vivo cocultures and mathematical modeling (Aim 2). We will leverage this knowledge to design CAF inhibitors and combine them with BRCA-specific therapies in cocultures and preclinical models, to address a major unmet clinical need to exploit CAF vulnerabilities for cancer therapy (Aim 3). This program provides a conceptual paradigm for understanding the principles of tumor microenvironment habitats, using BRCA as a testcase and four organs of clinical interest as model systems. This paradigm will be directly applicable to the major mutation classes and organ environments of cancer.