Extracellular Matrix Remodeling and the Control of Invasive Lobular Carcinoma Progression

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Proposal Summary Invasive lobular carcinoma (ILC) is the second most common subtype of breast cancer, and accounts for ~10% of all breast cancers. ILCs, highlighted by lost E-cadherin expression and diffuse, non-cohesive growth, are highly invasive, traversing the surrounding extracellular matrix (ECM) in a streaking pattern of single cells. While ILCs are relatively slow growing, preclusion of early detection, resistance to common chemo- and radiotherapies, and their highly invasive nature make them exceptionally difficult to eradicate, leading to significant patient morbidity and mortality. For ILCs to invade and metastasize, they must navigate the type I collagen-rich ECM surrounding the mammary epithelia, a process recently suggested to require proteolytic degradation, despite prior notions of proteolytic-independent migration. A specific membrane-bound matrix metalloproteinase capable of degrading type I collagen, MT1-MMP, has further been demonstrated to play a particularly crucial role in carcinoma invasion. To this end, MT1-MMP has been shown to be expressed in both ILC cells and surrounding cancer-associated fibroblasts (CAFs). Inversely, ILCs display an extensive accumulation of type I collagen deposition directly surrounding invasive lesions. However, it remains the subject of debate whether this increase in local ECM density confers pro- or anti-tumorigenic effects on ILCs and whether ECM deposition is primarily ILC cell- or CAF-derived. Further complicating the effects of ILC cell-ECM interactions in vivo, changes in MT1- MMP expression and ECM composition, in other systems, have been demonstrated to induce changes in transcription profiles. Therefore, this proposal aims to individually address each arm of the MT1-MMP/collagen axis characterizing its effects on ILC growth, invasion, and metastasis in vivo, in a manner specific to ILC cells and their surrounding CAFs. We hypothesize that both ILC cell- and CAF-derived MT1-MMP activity and ECM deposition influence ILC progression through physical remodeling of the ECM as well as via tumor-ECM induced transcriptomic changes. Experiments in Aim 1 will assess the role of ILC cell- and CAF-derived MT1-MMP during ILC progression using a combination of spontaneous and engrafted ILC models housing an Mt1-mmp floxed allele in mice and CRISPR-mediated MT1-MMP deletion in human ILC cells. Meanwhile, Aim 2 will separately assess the effects of altered ECM deposition in a cell-type specific manner, similarly, using spontaneous and engrafted ILC mouse models where a floxed Col1a1 allele has been inserted to disrupt collagen deposition by either carcinoma cells or the surrounding stroma. The experiments in Aims 1 & 2 will be further interrogated using advanced transcriptomic approaches including bulk and single-cell RNA sequencing to unbiasedly investigate effects on both targeted and surrounding cells. Collectively, this proposal aims to characterize the influences of the MT1-MMP/collagen axis on ILC progression and its associated transcriptional programs. Such insights will improve our understanding of the mechanisms underlying ILC growth, invasion, and metastasis, while simultaneously identifying potential targets for the tailored treatment of ILC in affected patients.