Noel, E. | bioRxiv Science

bioRxiv2019

Stromal Hedgehog pathway activation by IHH suppresses lung adenocarcinoma growth and metastasis by limiting reactive oxygen species

Activation of the Hedgehog (Hh) signaling pathway by mutations within its components drives the growth of several cancers. However, the role of Hh pathway activation in lung cancers has been controversial. We demonstrate that the Hh signaling pathway is activated in lung stroma in a paracrine manner. Genetic deletion of Shh in autochthonous murine lung adenocarcinoma had no effect on survival. Early abrogation of the pathway by an anti-SHH/IHH antibody 5E1 led to significantly worse survival with increased tumor and metastatic burden. Loss of IHH by in vivo CRISPR led to more aggressive tumor growth suggesting that IHH, not SHH, activates the pathway in stroma to drive its tumor suppressive effects - a novel role for IHH in the lung. Tumors from mice treated with 5E1 had decreased blood vessel density and increased reactive oxygen species (ROS). Treatment of KP mice with 5E1 and N-acetylcysteine, as a ROS scavenger, decreased tumor ROS levels, inhibited tumor growth and prolonged mouse survival suggesting that increased ROS levels from stromal Hh pathway inhibition spurred lung tumor growth. Thus, IHH induces stromal Hh pathway activation to suppress tumor growth and metastases, in part, by limiting ROS production.

cancer biology↗

bioRxiv2018

Sexual selection and inbreeding: two efficient ways to limit the accumulation of deleterious mutations

Theory and empirical data showed that two processes can boost selection against deleterious mutations, thus facilitating the purging of the mutation load: inbreeding, by exposing recessive deleterious alleles to selection in homozygous form, and sexual selection, by enhancing the relative reproductive success of males with small mutation loads. These processes tend to be mutually exclusive because sexual selection is reduced under mating systems that promote inbreeding, such as self-fertilization in hermaphrodites. We estimated the relative efficiency of inbreeding and sexual selection at purging the genetic load, using 50 generations of experimental evolution, in a hermaphroditic snail (Physa acuta). To this end, we generated lines that were exposed to various intensities of inbreeding, sexual selection (on the male function) and nonsexual selection (on the female function). We measured how these regimes affected the mutation load, quantified through the survival of outcrossed and selfed juveniles. We found that juvenile survival strongly decreased in outbred lines with reduced male selection, but not when female selection was relaxed, showing that male-specific sexual selection does purge deleterious mutations. However, in lines exposed to inbreeding, where sexual selection was also relaxed, survival did not decrease, and even increased for self-fertilized juveniles, showing that purging through inbreeding can compensate for the absence of sexual selection. Our results point to the further question of whether a mixed strategy combining the advantages of both mechanisms of genetic purging could be evolutionary stable.

evolutionary biology↗