Heino, J. | bioRxiv Science

bioRxiv2019

FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy

Gene copy number changes, cancer stem cell (CSC) increases, and platinum chemotherapy resistance contribute to poor prognosis in patients with recurrent high grade serous ovarian cancer (HGSOC). CSC phenotypes involving Wnt-{beta}-catenin and aldehyde dehydrogenase activities, platinum resistance, and tumor initiating frequency are here associated with spontaneous genetic gains, including genes encoding KRAS, MYC and FAK, in a new murine model of ovarian cancer (KMF). Noncanonical FAK signaling was sufficient to sustain human and KMF tumorsphere proliferation, CSC survival, and platinum resistance. Increased FAK tyrosine phosphorylation occurred in HGSOC patient tumors surviving neo-adjuvant platinum and paclitaxel chemotherapy and platinum resistant tumorspheres acquired FAK dependence for growth. Importantly, combining a pharmacologic FAK inhibitor with platinum overcame chemoresistance and triggered apoptosis in vitro and in vivo. Knockout, rescue, genomic and transcriptomic analyses collectively identified more than 400 genes regulated along a FAK/{beta}-catenin/Myc axis impacting stemness and DNA repair in HGSOC, with 66 genes gained in a majority of Cancer Genome Atlas samples. Together, these results support combinatorial testing of FAK inhibitors for the treatment of recurrent ovarian cancer.\n\nGraphical Summary\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC=\"FIGDIR/small/594184_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (52K):\norg.highwire.dtl.DTLVardef@20c737org.highwire.dtl.DTLVardef@1f714faorg.highwire.dtl.DTLVardef@823560org.highwire.dtl.DTLVardef@7e6219_HPS_FORMAT_FIGEXP M_FIG C_FIG Key PointsO_LIHigh grade serous ovarian carcinoma tumors contain PTK2 (FAK) 8q24.3 gains associated with prognostic differences.\nC_LIO_LIKMF, a new murine ovarian cancer model with K-Ras, Myc, and FAK gene gains and intrinsic platinum resistance.\nC_LIO_LIFAK activation in tumors surviving platinum chemotherapy promotes cancer stem cell survival.\nC_LIO_LIFAK facilitates a {beta}-catenin-Myc signaling axis controlling gene expression supporting platinum resistance.\nC_LIO_LIFAK activity is essential for KMF tumor growth and is a targetable cellular adaptation of platinum resistance.\nC_LI

cancer biology↗

bioRxiv2019

Community size affects the signals of selection and ecological drift on biodiversity

Ecological drift can override the effects of deterministic niche selection on small populations and drive the assembly of small communities. We tested the hypothesis that smaller local communities are more dissimilar among each other because of ecological drift than larger communities, which are mainly structured by niche selection. We used a unique, comprehensive dataset on insect communities sampled identically in a total of 200 streams in climatically different regions (Brazil and Finland) that differ in community size by fivefold. Null models allowed us to estimate the magnitude to which beta diversity deviates from the expectation under a random assembly process while taking differences in species richness and relative abundance into account, i.e., beta deviation. Beta diversity of small tropical communities was consistently higher but closer to null expectations than {beta}-diversity of large communities. However, although {beta}-deviation and community size were strongly related in both regions, the direction of the relationship varied according to dissimilarity metrics. While incidence-based {beta}-diversity was lower than expected (communities were less dissimilar than null expectations) and negatively related to community size in Brazil, abundance-based {beta}-diversity was higher than expected (communities were more dissimilar than null expectations) and positively related to community size in both regions. We suggest that ecological drift drives variation in small communities by increasing the chances of species with low abundance and narrow distribution to occur within the metacommunity. Also, while weak niche selection and high dispersal rates likely reduced variation in community structure among large tropical streams, niche selection was likely sufficient to cause non-random variations in the relative abundances of genera among large communities in both regions. Habitat destruction, overexploitation, pollution, and reductions in connectivity have been reducing the size of biological communities. These environmental pressures will make smaller communities more vulnerable to novel conditions and render community dynamics more unpredictable, as random demographic processes should prevail under these conditions. Incorporation of community size into ecological models should provide conceptual, empirical and applied insights into a better understanding of the processes driving changes in biodiversity.

ecology↗