Biology subjects

Etemad, B.

Publications and source records attributed to Etemad, B..

3 recordsLinked to original sources

bioRxiv2025

Non-cell-autonomous mechanisms of tumor initiation and relapse by chromosomal instability

Chromosomal instability (CIN) is a hallmark of cancer, and a primary cause of genetic heterogeneity in tumors. Depending on the degree of CIN and the affected tissue, CIN can promote or suppress tumor formation, and high CIN induction has been proposed as a therapeutic strategy. How CIN achieves these effects is unclear. Here we use a conditional mouse model of graded CIN in combination with longitudinal monitoring of DMBA/TPA-initiated skin tumors to show that low CIN increases the frequency of skin tumor initiation, while higher CIN accelerates onset and growth rates. Strikingly, gene recombination analysis of the tumors reveals that upon high CIN induction the fast-growing tumors originate from rare low CIN cells, suggesting a strong non-cell-autonomous effect of high CIN. Gene expression analysis and immunohistochemistry show that high CIN causes epidermal hyperplasia, immune evasion and a regenerative response that stimulates low CIN tumor growth beyond what is achieved by induction of low CIN alone. Such cell-extrinsic effects may be a common mechanism of tumor formation by CIN, as we observe it also in CIN-induced tumors of the intestine, breast and mesentery. When high CIN is induced in established skin tumors, mimicking CIN-based therapy, tumors regress but relapse quickly. Relapsed tumors, too, arose from rare low CIN cells. Our findings have implications for our understanding of the contributions of CIN to cancer initiation and progression and give caution to the rationale for CIN therapies. Significance statementChromosomal instability (CIN) is a source of genetic diversity in cancer. Different degrees of CIN can be highly oncogenic or tumor suppressive, the latter being a rationale for CIN-based therapies. Using a mouse model for precise control of CIN levels, we show that low CIN promotes tumor initiation, while moderate CIN accelerates both initiation and tumor growth. Surprisingly, moderate CIN acts through its effects on the surrounding tissue rather than directly within tumor cells, by triggering a regenerative response accompanied by immune evasion. When very high CIN is induced in existing tumors, tumors initially regress but rapidly relapse. These findings inform on the contributions of CIN to cancer initiation and progression and give caution to the rationale for CIN therapies.

cancer biology↗

bioRxiv2025

A New Type of Nonsuppressible Viremia Produced by HIV-Infected Macrophage

BackgroundHIV-1 RNA typically declines rapidly after initiation of antiretroviral therapy (ART); often reaching undetectable levels within a few weeks and remaining undetectable by standard assays. However, some patients on ART have persistent nonsuppressible viremia (NSV) that does not respond to treatment optimization or intensification. NSV can emerge at the time of ART initiation (primary NSV) or after being ART-suppressed (secondary NSV). Here, we examine mechanisms producing primary NSV in four people on ART. MethodsBlood samples were collected from four participants who, despite being adherent to ART, required approximately a year or more to become virologically suppressed. Viral RNA and proviral DNA genomes were sequenced to examine HIV-1 drug resistance, genome intactness and genetic diversity. The ability of HIV-1 Envs to facilitate efficient entry into cells expressing low levels of CD4 (a proxy for macrophage tropism) was assessed. ResultsBefore ART, the blood contained HIV-1 RNA genomes that were adapted to replication in CD4+ T cells and rapidly decayed after ART initiation. During ART, the blood contained HIV-1 genomes that were drug sensitive, genetically diverse, macrophage-tropic, not evolving and often had defects in vpr. ConclusionsOur results suggest that in individuals with primary NSV, ART stopped virus replication, but large pools of long-lived, HIV-infected macrophage continued to produce virus. This is mechanistically distinct from secondary NSV produced by CD4+ T cell clones. In addition, defects in vpr independently accumulation in macrophage-tropic lineages found in three participants, suggesting that vpr may impact survival of, or virus production from, HIV-infected macrophage. SUMMARYPeople with HIV-1 on ART can experience persistent, nonsuppressible viremia (NSV). We identified four people with a previously uncharacterized form of NSV that emerged at the time of ART initiation (primary NSV) and is notable for its genetic diversity, drug sensitivity, and macrophage tropism. This is mechanistically distinct from previously described cases of NSV produced by CD4+ T cells in people who were previously ART-suppressed (secondary NSV).

microbiology↗

bioRxiv2018

Spindle checkpoint silencing at kinetochores with submaximal microtubule occupancy

The spindle assembly checkpoint (SAC) ensures proper chromosome segregation by monitoring kinetochore-microtubule interactions. SAC proteins are shed from kinetochores once stable attachments are achieved. Human kinetochores consist of hundreds of SAC protein recruitment modules and bind up to 20 microtubules, raising the question how the SAC responds to intermediate attachment states. We show that the RZZS-MAD1/2 module of the SAC is removed from kinetochores at low microtubule occupancy and remains absent at higher occupancies, while the BUB1/R1 module is retained at substantial levels irrespective of attachment states. Artificially tuning the affinity of kinetochores for microtubules further shows that ~50% occupancy is sufficient to shed MAD2 and silence the SAC. Kinetochores thus responds as a single unit to shut down SAC signaling at submaximal occupancy states, but retains one SAC module. This may ensure continued SAC silencing on kinetochores with fluctuating occupancy states while maintaining the ability for fast SAC re-activation.

cell biology↗