Disrupting Ribosome Biogenesis to Break Chemoresistance in Breast Cancer

Metastatic breast cancer disease continues to defy even the most aggressive therapeutic strategies. The resilience of these cancers is not simply a matter of genetic mutations; it is deeply rooted in their extraordinary capacity for adaptation. Central to this adaptability is the process known as epithelial-to-mesenchymal transition (EMT). Through EMT, epithelial cancer cells shed their organized, adhesive characteristics and acquire more resilient survival as they transition into a mesenchymal state.  Moreover, and as critical, though often overlooked, is the reverse process, the mesenchymal-to-epithelial transition (MET), which enables these cells to re-establish rapidly growing new colonies. Together, EMT and MET form a fluid and dynamic system of phenotypic shifts that not only drives cancer progression but also undermines the effectiveness of conventional chemo-treatments by making tumor cells far more stress-tolerant.

For years, research efforts have attempted to interrupt this cycle, often by targeting key signaling pathways such as TGF-β, Wnt, and Notch, or by suppressing the expression of master regulators like Snail, Twist, and Zeb1, but with limited success. A major complication is the paradox that arises when EMT is blocked; this often triggers MET, which, rather than halting progression, actually facilitates colonization of drug-resistant cells and tumor regrowth. This frustrating cycle has made it abundantly clear that simply targeting one end of the spectrum is insufficient. What’s needed is a way to disrupt the very foundation that allows cancer cells to shift between these states so fluidly. To this end, a new research paper published in eLife Journal and conducted by Assistant Professor Yi Ban (NYU), Dr. Yue Zou, Dr. Yingzhuo Liu, Ms. Sharrel Lee, Assistant Professor Robert Bednarczyk (University of Chicago), and Associate Professor Dingcheng Gao (Weill Cornell Medicine),  together with Dr. Jianting Sheng, Dr. Yuliang Cao, and Professor Stephen T C Wong (Houston Methodist Hospital), the researchers developed a novel therapeutic strategy for overcoming chemoresistance in breast cancer by targeting ribosome biogenesis (RiBi). Instead of focusing on blocking specific signaling pathways or surface markers, they discovered that the ability of cancer cells to transition between epithelial and mesenchymal states (EMT and MET) critically depends on their capacity to ramp up protein production through enhanced RiBi.

To prove their hypothesis, the researchers turned to the Tri-PyMT EMT lineage-tracing system, which is a sophisticated tool specifically designed to capture how tumor cells shift their identity over time. This model uses an irreversible fluorescence switch, permanently marking cells as they transition from an epithelial state to a mesenchymal one. Interestingly, when the authors cultured these cells under conditions known to promote EMT, they noticed a small fraction of cells lit up with both fluorescent markers simultaneously—these were the so-called “Double+” cells, caught somewhere between their old and new identities. Rather than being a mere curiosity, these cells seemed to represent a critical phase of active change, precisely marking the moment when tumor cells become resistant to therapy. The team isolated these Double+ cells and performed bulk RNA sequencing, finding that genes involved in ribosome biogenesis were highly upregulated. To dig deeper, they turned to single-cell RNA sequencing, hoping for a more granular view. As it turned out, transitional cells consistently showed higher ribosomal gene expression than their fully committed epithelial or mesenchymal counterparts. But correlation alone wasn’t enough. The researchers wanted to know: is this surge in ribosome production vital for the transition to happen? To test this, they used RNA Polymerase I inhibitors—BMH21 and CX5461—to directly block ribosome biogenesis. Remarkably, the transition stalled. Cells treated with these inhibitors clung to their epithelial markers and failed to fully express key mesenchymal proteins like Vimentin and Snail, and vice versa. Genetic knockdown of ribosomal proteins Rps24 and Rps28 produced much the same result, reinforcing the idea that, without the ability to rapidly manufacture new proteins, tumor cells simply couldn’t complete their transformation in either direction. The logical next question was whether this blockade could make tumors more vulnerable to treatment. The research team combined BMH21 with cyclophosphamide, and a striking synergistic effect was observed — the combination was far more lethal to cancer cells than either treatment alone. Encouragingly, this success extended to mouse models, where co-treatment not only reduced overall tumor burden but also suppressed both epithelial and mesenchymal tumor cell populations.

In conclusion, the new study reignited the underlying question of how to weaken one of cancer’s most formidable defenses—its Epithelial-Mesenchymal Plasticity. For years, the field has focused mainly on chasing down specific signaling pathways or suppressing individual molecular markers, with limited long-term success. This research took a different approach. Rather than attacking cancer cells at the surface level, the investigators turned their attention to a fundamental process that underpins the entire phenomenon of state switching: ribosome biogenesis. In doing so, they uncovered a critical dependency that had gone largely unnoticed. Cancer cells, it turns out, can’t easily shift between epithelial and mesenchymal identities without first ramping up their capacity to produce new proteins. This isn’t just a biochemical side note—it’s a core requirement for executing the extensive molecular and structural remodeling these transitions demand.

The broader implications of these findings are hard to ignore. Most notably, this work offers a strong rationale for combining ribosome biogenesis inhibitors with conventional chemotherapy, not to replace existing treatments, but to strategically weaken cancer cells exactly when they’re at their most vulnerable—during the exhausting process of phenotypic transition. By hitting them at this critical juncture, the chances of preventing or at least delaying the emergence of highly drug-resistant populations are dramatically increased.

Another key finding of the authors’ work is the importance of treatment timing and the discovery that RiBi activity rises only briefly during EMT and MET highlights a narrow but potentially powerful therapeutic window. Instead of applying treatments uniformly, as is so often the case, this suggests that carefully timed interventions could more effectively disrupt the plasticity that allows cancer cells to adapt and survive. However, the timing of catching the peak of the transitioning cells during treatment requires further investigation. In many ways, this reframes treatment scheduling from a matter of convenience to a critical tactical decision. Perhaps equally important, the authors raise the intriguing possibility that ribosome biogenesis itself could serve as a prognostic marker. Patients with tumors exhibiting high RiBi activity might be precisely the individuals most likely to benefit from this combinatorial approach. Stepping back, what this research really challenges is the long-held belief that it’s enough to target cancer cells in one state or another. Instead, it points to a more disruptive—and arguably more effective—strategy: stripping cancer cells of their ability to switch identities altogether.